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Psychedelics in Psychiatry–Keeping the Renaissance From Going Off the Rails



There is a resurgence, some say renaissance, of clinical research on psychedelic substances after decades of dormancy. Recent studies have produced findings suggesting psychedelics may demonstrate substantial efficacy for serious psychiatric conditions such as mood and substance use disorders. As a result, ongoing clinical trials with the psychedelic psilocybin have been given the Breakthrough Therapy designation by the US Food and Drug Administration that could result in medical approval for major depressive disorder and/or treatment-resistant depression.
Psychedelics in Psychiatry—Keeping the Renaissance From
Going Off the Rails
There is a resurgence, some say renaissance, of clini-
cal research on psychedelic substances after decades of
dormancy. Recentstudies have produced findings sug-
gesting psychedelics may demonstrate substantial effi-
cacy for serious psychiatric conditions such as mood and
substance use disorders. As a result, ongoing clinical trials
with the psychedelic psilocybin have been given the
Breakthrough Therapy designation by the US Food and
Drug Administration that could result in medical ap-
proval for major depressive disorder and/ortreatment-
resistant depression.
This new period of psychedelic research, ongoing
since at least 2006, has now lasted for about the same
length of time as psychedelic research in the 1950s and
1960s did before it ground to a halt. As contemporary
psychedelic research results accrue, the field may be fac-
ing a fork in the road to clinical applications. One path
forward allows for the same kinds of exuberance, uto-
pian thinking, and uneven clinical approaches that con-
tributed to ending the previous period of research. Com-
bined with the contemporary tendency to politicize
science, the possibility of a repeat of the 1960s repre-
sents a significant concern. Another path forward, a more
careful and systematic one, involves the appropriate in-
tegration of psychedelic treatments into existing evi-
dence-based psychiatric paradigms such as psycho-
therapy and pharmacotherapy.
This Viewpoint offers perspectives on how the psy-
chedelic research renaissance can stay on the path that
leads to the integration of these medications into the
standard of care rather than recapitulating the ethical and
sociopolitical problems that led to the previous period
of research going off the rails.
History of Psychedelic Research
Psilocybin is a psychedelic compound in certain mush-
rooms, which have been used in sacred ceremonies
among indigenous peoples in Mexico and elsewhere for
centuries. Other psychedelic compounds, such as mes-
caline and DMT (N,N-dimethyltryptamine), have like-
wise been used for hundreds or thousands of years in
ritual contexts. The psychedelic LSD (lysergic acid di-
ethylamide), which the Swiss chemist Albert Hofmann
synthesized in 1938, led to innovations in understand-
ing serotonin pharmacology and, eventually (albeit in-
directly), to the development of therapeutics that modu-
late serotonin function such as selective serotonin
reuptake inhibitors.
During a period in the 1950s and 1960s, research es-
tablished that psychedelic substances produce substan-
tially altered states of consciousness. This era of re-
search showed psychedelics as having considerable
promise in the treatment of depression in patients with
cancer and alcohol use disorder. However, in the late
1960s, clinical research on psychedelics was function-
ally prohibited because of burdensome governmental
regulations, the perceived association of the sub-
stances with an anti-establishment counterculture, mis-
perception of risk resulting from negatively biased me-
dia coverage, and lapses in research ethics.
Recent Research
After several decades of inactivity in the US, psyche-
delic research in healthy psychedelic-naive partici-
pants was restarted at Johns Hopkins in 2000. Studies
have focused on the serotonergic psychedelics (espe-
cially psilocybin), so called because these compounds
function as partial 5-HT
serotonin receptor agonists.
Many studies have confirmed the low toxicity and mini-
mal addiction potential of serotonergic and other
The study most often cited as restarting the cur-
rent period of psychedelic research was a double-blind
randomized clinical trial that examined psilocybin ad-
ministered in a supportive setting. The intervention re-
sulted in long-term increases in positive mood, life sat-
isfaction, and prosocial behavior in healthy participants.
Two double-blind randomized clinical trials on patients
with life-threatening cancer diagnoses showed sus-
tained decreases in anxiety and depression.
tional research in clinical populations has suggested ef-
ficacy for treatment of mood disorders and substance
use disorders.
These and other recent and ongoing
studies suggest the potential for psychedelics to be used
as new and effective treatments for a range of psychi-
atric conditions.
Dead Ends
Despite this promise, cultural forces such as those that
occurred in the 1960s may threaten contemporary re-
search progress and the clinical application of psyche-
delics. For example, numerous recent popular press
books, websites, podcasts, and media reports have un-
critically promoted presumed benefits of psychedelics.
Patient demand is growing, as is interest in the general
population, with the possibility that expectations are out-
pacing the current data on what outcomes can be con-
fidently foreseen. Psychedelics are neither a cure for
mental disorders nor a quick fix for an unfulfilled life and
should not be portrayed as a panacea. Ominously, pro-
psychedelic subcultures are increasingly fostering uto-
pian visions for society based on research findings that,
while intriguing, still must be considered preliminary.
If psychedelic research is going to avoid another pe-
riod of prohibition, we must learn from the lessons of the
past. It is critically important that the medical and sci-
David B. Yaden,PhD
Department of
Psychiatry and
Behavioral Sciences,
Johns Hopkins
University School of
Medicine, Baltimore,
Maryland; and Center
for Psychedelic and
Research, Johns
Hopkins University
School of Medicine,
Baltimore, Maryland.
Mary E. Yaden,MD
Department of
School of Medicine,
University of
Roland R. Griffiths,
Department of
Psychiatry and
Behavioral Sciences,
Johns Hopkins
University School of
Medicine, Baltimore,
Maryland; and Center
for Psychedelic and
Research, Johns
Hopkins University
School of Medicine,
Baltimore, Maryland.
Author: Roland R.
Griffiths, PhD,
Hopkins Center for
Psychedelic and
Research, 5510 Nathan
Shock Dr, Baltimore,
MD 21224 (rgriff@jhmi.
Opinion (Reprinted) JAMA Psychiatry Published online December 2, 2020 E1
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entific communities be vigilant in opposing the conflation of sci-
ence with larger cultural agendas, as occurred in the 1960s with the
blending of psychedelics into the antiwar and other anti-
establishment movements. The enthusiasms that attend such agen-
das should not be allowed to supersede the scientific and regula-
tory processes meant to carefully vet these substances and their
application in a variety of mood and behavioral disorders.
A Way Forward
More randomized clinical trials are necessary to replicate and ex-
tend the promising findings of open-label trials and to better un-
derstand contraindications and other potential risks. Furthermore,
additional studies will be required to better understand the mecha-
nisms by which psychedelics exert their therapeutic effects, ideal
dosing schedules, selection of the most effective compounds, and
optimal clinical management. The lure of the approval of the clini-
cal use of psychedelics raises the possibility that a vast arrayof eclec-
tic and untested psychotherapeutic techniques may be applied in
conjunction with medication administration. Considering that psy-
chedelic experiences are known to be strongly influenced by expec-
tations and the context (ie, set and setting) and that such experi-
ences sometimes result in major shifts in worldview, adding
psychedelics to fringe or unproven psychotherapeutic paradigms
may increase the risk of iatrogenic harm. The safest and most effec-
tive psychedelic treatment protocols will likely be those that inte-
grate existing evidence-based interventions and psychotherapies.
Psychiatric treatments have seen only modest innovation for de-
cades. Research on psychedelics is pointing to the potential for new
treatment options for a variety of psychiatric conditions. However,
as testing and clinical applications expand, it is still possible for re-
searchers and clinicians to squander this opportunity.The word re-
naissance comes from the French wordfor rebir th; however, this may
be somewhat of a misnomer as it has been more than 2 decades since
clinical psychedelic research resumed in the US. We believethis new
era of psychedelic research is no longer being reborn but rather com-
ing into maturity. Whether this era of psychedelic research will con-
clude with another scientific and clinical dead-end period of prohi-
bition or move ahead into a productive time of mainstream research
and clinical application remains to be seen. We owe it to the next
generation of researchers and clinicians, and to the millions of pa-
tients with mood and substance use disorders who may benefit from
these treatments, to ensure that no exceptions be made in the stan-
dards of research or clinical application for psychedelics, regard-
less of their seemingly exceptional potential.
Published Online: December 2, 2020.
Conflict of Interest Disclosures: Dr Griffiths
reports grants from the Steven and Alexandra
Cohen Foundation and from Tim Ferris, Matt
Mullenweg, Blake Mycoskie, and Craig Nerenberg
for funding the Johns Hopkins Center for
Psychedelic and Consciousness Research (CPCR)
during the conduct of the study; grants from the
Riverstyx Foundation, a crowdsourced funding
campaign organized by Tim Ferriss, and National
Institute on Drug Abuse (grant R01DA03889) for
research support outside the submitted work;
personal fees from the Heffter Research Institute
(HRI) to cover travel costs as member of the board
of directors of HRI outside the submitted work; and
is site principal investigator for a multisite trial of
psilocybin-facilitated treatment of major depressive
disorder, which is sponsored by the Usona Institute.
No other disclosures were reported.
Funding/Support: Support for Drs D. Yadenand
Griffiths through the Johns Hopkins Center for
Psychedelic and Consciousness Research was
provided by Tim Ferriss, Matt Mullenweg, Blake
Mycoskie, Craig Nerenberg, and the Steven and
Alexandra Cohen Foundation. Dr M. Yaden was
supported by the National Institute of Mental
Health (grant R25MH119043).
Role of the Funder/Sponsor:The funders had no
role in the design and conduct of the study;
collection, management, analysis, and
interpretation of the data; preparation, review, or
approval of the manuscript; and decision to submit
the manuscript for publication.
Additional Contributions: We thank James B.
Potash, MD (Department of Psychiatry and
Behavioral Sciences, Johns Hopkins University
School of Medicine), for his helpful comments and
suggestions. He was not compensated.
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Opinion Viewpoint
E2 JAMA Psychiatry Published online December 2, 2020 (Reprinted)
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... The massive public enthusiasm about psychedelics-perhaps to a degree unprecedented in psychiatry-stems not only from recent encouraging studies, but also from the convergence of activism, media attention, and commercial interests stimulating robust excitement. The result has been public beliefs about the benefits and risks of psychedelics that may outstrip the preliminary nature of both the clinical and public health evidence (Phelps et al., 2022;Smith and Appelbaum, 2021b;Yaden et al., 2021). This has been embodied in state and local initiatives to decriminalize or legalize possession of psychedelics (discussed in more detail below), J o u r n a l P r e -p r o o f whether for treatment purposes as in Oregon or for recreational use as has been proposed in California. ...
... Most parties agree that psychedelics' potential harms and abuse potential is low relative to many other controlled substances (Johnson et al., 2018;Nutt et al., 2010). Yet, they diverge about how best to balance potential risks of legalization and decriminalization-whether through rescheduling or other means-with the potential effects on further research, potential benefits of increased access, and concerns about overcriminalization of substance use in the United States (Alpert, 2021;Campbell and Williams, 2021;Downey et al., 2021;Marks, 2021;Marks and Cohen, 2021;Smith and Appelbaum, 2021a;Smith and Appelbaum, 2021b;Yaden et al., 2021). Perhaps ironically, one concern is that while Schedule I status has been thought to have made research on psychedelics more challenging (Belouin and Henningfield, 2018;Nutt et al., 2013), rapid expansion of access J o u r n a l P r e -p r o o f with inadequate data-gathering and poor fidelity treatment may risk the ability to generate further, needed research (Yaden et al., 2021). ...
... Yet, they diverge about how best to balance potential risks of legalization and decriminalization-whether through rescheduling or other means-with the potential effects on further research, potential benefits of increased access, and concerns about overcriminalization of substance use in the United States (Alpert, 2021;Campbell and Williams, 2021;Downey et al., 2021;Marks, 2021;Marks and Cohen, 2021;Smith and Appelbaum, 2021a;Smith and Appelbaum, 2021b;Yaden et al., 2021). Perhaps ironically, one concern is that while Schedule I status has been thought to have made research on psychedelics more challenging (Belouin and Henningfield, 2018;Nutt et al., 2013), rapid expansion of access J o u r n a l P r e -p r o o f with inadequate data-gathering and poor fidelity treatment may risk the ability to generate further, needed research (Yaden et al., 2021). ...
Classic psychedelics and related substances have shown promising initial research results. However, they raise a number of relatively novel ethical and policy challenges in light of their psychoactive properties, their emergence from the unregulated "underground" settings in which they have been used, their rapid commercialization, and the means and speed with which they are moving from Schedule 1 status to legalized use. All of these issues are affected by the current limits to the evidence base on use of psychedelics. Here we survey these novel challenges, illustrating the issues raised regarding each, and offering suggestions for how to address them.
... Not only in non-medical users but also in patients, researchers, and clinicians, they may evoke strong expectation biases, increased suggestibility, and idealization. The latter is also illustrated by the increasing popularization of these substances among various groups (Yaden et al., 2021;Anderson et al., 2020). ...
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... [43][44][45][46] Despite these promising findings, we caution that more research is needed, especially better controlled and larger trials before firm conclusions can be drawn regarding these seemingly highly positive effects. 47 With these caveats in place, we believe that the current evidence suggests that the subjective effects of psychedelics pose some risk of inducing a challenging and stress inducing experience that may in some cases have lingering negative psychological consequences, but that the vast majority of participants report highly beneficial effects that are in many cases considered extraordinarily meaningful. ...
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Evidence suggests that psychedelics bring about their therapeutic outcomes in part through the subjective or qualitative effects they engender and how the individual interprets the resulting experiences. However, psychedelics are contraindicated for individuals who have been diagnosed with certain mental illnesses, on the grounds that these subjective effects may be disturbing or otherwise counter-therapeutic. Substantial resources are therefore currently being devoted to creating psychedelic substances that produce many of the same biological changes as psychedelics, but without their characteristic subjective effects. In this article, we consider ethical issues arising from the prospect of such potential 'non-subjective' psychedelics. We are broadly supportive of efforts to produce such substances for both scientific and clinical reasons. However, we argue that such non-subjective psychedelics should be reserved for those special cases in which the subjective effects of psychedelics are specifically contraindicated, whereas classic psychedelics that affect subjective experience should be considered the default and standard of care. After reviewing evidence regarding the subjective effects of psychedelics, we raise a number of ethical concerns around the prospect of withholding such typically positive, meaningful, and therapeutic experiences from most patients.
... Misinformation about the dangers of LSD circulated via mass media during the '60s is believed to have contributed to more 'bad trips' during this era also in the community, through negatively affecting the mindset and expectations of people about to use the drug (Bunce, 1979). Psychedelics are nowadays generally portrayed in a more positive light in the media, but concerns have been raised that overly positive media reports could understate risks (Carhart-Harris et al., 2018;Yaden et al., 2020). National surveys have shown trends of increasing LSD use over the past decade (gov. ...
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Background Recreational lysergic acid diethylamide (LSD) use is growing in popularity amid increasing research interest on psychedelics and their possible therapeutic potential yet; the potent psychotropic effects of LSD may result in adverse reactions and behaviour. Aims This study aimed to investigate the 12-month incidence and nature of LSD-related adverse experiences resulting in emergency medical treatment (EMT) seeking in an international sample of people reporting LSD use. Methods We use data from the 2017 Global Drug Survey – a large anonymous online survey on patterns of drug use conducted between November 2016 and January 2017. Results Out of 10,293 past-year LSD users, 102 (1.0%) reported seeking EMT, with a per-event risk estimate of 0.2%. Younger age, comorbid mental health conditions and higher frequency of use were associated with increased risk of EMT seeking. The most common symptoms were psychological, including anxiety, panic and confusion, with the most common explanatory factors cited by respondents being poor ‘setting’ and ‘mindset’. Most responders reported feeling back to normal within 24 h, but 11 participants experienced persistent issues after 4 weeks. Conclusion The results suggest that LSD is a relatively safe drug in recreational settings. Adverse reactions are typically short-lived, self-limiting and psychological in nature. Sub-optimal set and setting were commonly reported as suspected contributory factors. Within clinical settings, patient screening, preparatory sessions and supervision should reduce these acute risks considerably.
... There are specific psychedelics of reemerging interest in psychiatry and neuroscience, including psilocybin, ayahuasca, DMT, LSD, and other synthesized medicinal chemicals that possess hallucinogenic properties, such as ketamine. There has been some recent evidence-based on randomized controlled trials (RCTs)-on the therapeutic effectiveness of those chemicals at the micro-dose range to manage debilitating conditions, including cognitive impairment, Alzheimer's disease, and refractory psychiatric entities within the neurotic spectrum, including the post-traumatic stress disorder (PTSD), recalcitrant obsessive-compulsive disorder (OCD), panic disorder, and refractory depression [10][11][12][13]. ...
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... Clinical trials have demonstrated the therapeutic potential of psilocybin on both mood Griffiths et al., 2016;Ross et al., 2016;Davis et al., 2021) and substance use disorders (Johnson et al., 2014;Bogenschutz et al., 2015). Further safety and effectiveness trials are needed (Yaden et al., 2021d), but it is possible that psilocybin (and perhaps other classic psychedelics) will be approved for clinical use in the next few years. While current psychotherapeutic and pharmacological treatments are effective, additional treatment options are needed for those suffering from mood and substance use disorders. ...
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This paper provides a critical review of several possible mechanisms at different levels of analysis underlying the effects and therapeutic potential of psychedelics. At the (1) biochemical level, psychedelics primarily affect the 5-HT2a receptor, increase neuroplasticity, offer a critical period for social reward learning and have anti-inflammatory properties. At the (2) neural level, psychedelics have been associated with reduced efficacy of thalamo-cortical filtering, the loosening of top-down predictive signaling and an increased sensitivity to bottom-up prediction errors, and activation of the claustro-cortical-circuit. At the (3) psychological level, psychedelics have been shown to induce altered and affective states, they affect cognition, induce belief change, exert social effects and can result in lasting changes in behavior. We outline the potential for a unifying account of the mechanisms underlying psychedelics and contrast this with a model of pluralistic causation. Ultimately, a better understanding of the specific mechanisms underlying the effects of psychedelics could allow for a more targeted therapeutic approach. We highlight current challenges for psychedelic research and provide a research agenda to foster insight in the causal-mechanistic pathways underlying the efficacy of psychedelic research and therapy.
Psychedelic substances have played important roles in diverse cultures, and ingesting various plant preparations to evoke altered states of consciousness has been described throughout recorded history. Accounts of the subjective effects of psychedelics typically focus on spiritual and mystical-type experiences, including feelings of unity, sacredness, and transcendence. Over the past two decades, there has been increasing interest in psychedelics as treatments for various medical disorders, including chronic pain. Although concerns about adverse medical and psychological effects contributed to their controlled status, contemporary knowledge of psychedelics suggests that risks are relatively rare when patients are carefully screened, prepared, and supervised. Clinical trial results have provided support for the effectiveness of psychedelics in different psychiatric conditions. However, there are only a small number of generally uncontrolled studies of psychedelics in patients with chronic pain (e.g., cancer pain, phantom limb pain, migraine, and cluster headache). Challenges in evaluating psychedelics as treatments for chronic pain include identifying neurobiologic and psychosocial mechanisms of action and determining which pain conditions to investigate. Truly informative proof-of-concept and confirmatory randomized clinical trials will require careful selection of control groups, efforts to minimize bias from unblinding, and attention to the roles of patient mental set and treatment setting. Perspective: There is considerable promise for the use of psychedelic therapy for pain, but evidence-based recommendations for the design of future studies are needed to ensure that the results of this research are truly informative.
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In this study, we describe the development and initial validation of two psychometric scales for measuring psychedelic integration. Psychedelic integration refers to the post-acute period of time following psychedelic drug administration. We created the Integration Engagement Scale (IES) to capture positive behavioral engagement with integration and the Experienced Integration Scale (EIS) to capture internal aspects of feeling integrated. These scales were developed to measure post-acute psychedelic administration dynamics in order to inform the creation of enhanced integration support and to help refine a general conceptual understanding of the construct of psychedelic integration. The scales are brief and face valid instruments designed for practical use in applied and research settings. Scale items were generated and refined using the Iterative Process Model of scale development, with input from psychedelics experts and clinicians. Content validity, internal structure, and reliability were assessed via expert surveys, content validity analysis, cognitive interviewing, convergent validity analysis, exploratory factor analysis, and confirmatory factor analysis. The data indicates the scales are valid and reliable measurements of the behavioral and experiential forms of Psychedelic Integration.
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Cancer patients often develop chronic, clinically significant symptoms of depression and anxiety. Previous studies suggest that psilocybin may decrease depression and anxiety in cancer patients. The effects of psilocybin were studied in 51 cancer patients with life-threatening diagnoses and symptoms of depression and/or anxiety. This randomized, double-blind, cross-over trial investigated the effects of a very low (placebo-like) dose (1 or 3 mg/70 kg) vs. a high dose (22 or 30 mg/70 kg) of psilocybin administered in counterbalanced sequence with 5 weeks between sessions and a 6-month follow-up. Instructions to participants and staff minimized expectancy effects. Participants, staff, and community observers rated participant moods, attitudes, and behaviors throughout the study. High-dose psilocybin produced large decreases in clinician- and self-rated measures of depressed mood and anxiety, along with increases in quality of life, life meaning, and optimism, and decreases in death anxiety. At 6-month follow-up, these changes were sustained, with about 80% of participants continuing to show clinically significant decreases in depressed mood and anxiety. Participants attributed improvements in attitudes about life/self, mood, relationships, and spirituality to the high-dose experience, with >80% endorsing moderately or greater increased well-being/life satisfaction. Community observer ratings showed corresponding changes. Mystical-type psilocybin experience on session day mediated the effect of psilocybin dose on therapeutic outcomes. Trial Registration identifier: NCT00465595
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Background: Clinically significant anxiety and depression are common in patients with cancer, and are associated with poor psychiatric and medical outcomes. Historical and recent research suggests a role for psilocybin to treat cancer-related anxiety and depression. Methods: In this double-blind, placebo-controlled, crossover trial, 29 patients with cancer-related anxiety and depression were randomly assigned and received treatment with single-dose psilocybin (0.3 mg/kg) or niacin, both in conjunction with psychotherapy. The primary outcomes were anxiety and depression assessed between groups prior to the crossover at 7 weeks. Results: Prior to the crossover, psilocybin produced immediate, substantial, and sustained improvements in anxiety and depression and led to decreases in cancer-related demoralization and hopelessness, improved spiritual wellbeing, and increased quality of life. At the 6.5-month follow-up, psilocybin was associated with enduring anxiolytic and anti-depressant effects (approximately 60-80% of participants continued with clinically significant reductions in depression or anxiety), sustained benefits in existential distress and quality of life, as well as improved attitudes towards death. The psilocybin-induced mystical experience mediated the therapeutic effect of psilocybin on anxiety and depression. Conclusions: In conjunction with psychotherapy, single moderate-dose psilocybin produced rapid, robust and enduring anxiolytic and anti-depressant effects in patients with cancer-related psychological distress. Trial registration: Identifier: NCT00957359.
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Background: Psilocybin is a serotonin receptor agonist that occurs naturally in some mushroom species. Recent studies have assessed the therapeutic potential of psilocybin for various conditions, including end-of-life anxiety, obsessive-compulsive disorder, and smoking and alcohol dependence, with promising preliminary results. Here, we aimed to investigate the feasibility, safety, and efficacy of psilocybin in patients with unipolar treatment-resistant depression. Methods: In this open-label feasibility trial, 12 patients (six men, six women) with moderate-to-severe, unipolar, treatment-resistant major depression received two oral doses of psilocybin (10 mg and 25 mg, 7 days apart) in a supportive setting. There was no control group. Psychological support was provided before, during, and after each session. The primary outcome measure for feasibility was patient-reported intensity of psilocybin's effects. Patients were monitored for adverse reactions during the dosing sessions and subsequent clinic and remote follow-up. Depressive symptoms were assessed with standard assessments from 1 week to 3 months after treatment, with the 16-item Quick Inventory of Depressive Symptoms (QIDS) serving as the primary efficacy outcome. This trial is registered with ISRCTN, number ISRCTN14426797. Findings: Psilocybin's acute psychedelic effects typically became detectable 30-60 min after dosing, peaked 2-3 h after dosing, and subsided to negligible levels at least 6 h after dosing. Mean self-rated intensity (on a 0-1 scale) was 0·51 (SD 0·36) for the low-dose session and 0·75 (SD 0·27) for the high-dose session. Psilocybin was well tolerated by all of the patients, and no serious or unexpected adverse events occurred. The adverse reactions we noted were transient anxiety during drug onset (all patients), transient confusion or thought disorder (nine patients), mild and transient nausea (four patients), and transient headache (four patients). Relative to baseline, depressive symptoms were markedly reduced 1 week (mean QIDS difference -11·8, 95% CI -9·15 to -14·35, p=0·002, Hedges' g=3·1) and 3 months (-9·2, 95% CI -5·69 to -12·71, p=0·003, Hedges' g=2) after high-dose treatment. Marked and sustained improvements in anxiety and anhedonia were also noted. Interpretation: This study provides preliminary support for the safety and efficacy of psilocybin for treatment-resistant depression and motivates further trials, with more rigorous designs, to better examine the therapeutic potential of this approach. Funding: Medical Research Council.
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Psychedelics (serotonergic hallucinogens) are powerful psychoactive substances that alter perception and mood and affect numerous cognitive processes. They are generally considered physiologically safe and do not lead to dependence or addiction. Their origin predates written history, and they were employed by early cultures in many sociocultural and ritual contexts. After the virtually contemporaneous discovery of (5R,8R)-(+)-lysergic acid-N,N-diethylamide (LSD)-25 and the identification of serotonin in the brain, early research focused intensively on the possibility that LSD and other psychedelics had a serotonergic basis for their action. Today there is a consensus that psychedelics are agonists or partial agonists at brain serotonin 5-hydroxytryptamine 2A receptors, with particular importance on those expressed on apical dendrites of neocortical pyramidal cells in layer V. Several useful rodent models have been developed over the years to help unravel the neurochemical correlates of serotonin 5-hydroxytryptamine 2A receptor activation in the brain, and a variety of imaging techniques have been employed to identify key brain areas that are directly affected by psychedelics. Recent and exciting developments in the field have occurred in clinical research, where several double-blind placebo-controlled phase 2 studies of psilocybin-assisted psychotherapy in patients with cancer-related psychosocial distress have demonstrated unprecedented positive relief of anxiety and depression. Two small pilot studies of psilocybinassisted psychotherapy also have shown positive benefit in treating both alcohol and nicotine addiction. Recently, blood oxygen level–dependent functional magnetic resonance imaging and magnetoencephalography have been employed for in vivo brain imaging in humans after administration of a psychedelic, and results indicate that intravenously administered psilocybin and LSD produce decreases in oscillatory power in areas of the brain’s default mode network. © 2016 by The American Society for Pharmacology and Experimental Therapeutics.
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Several lines of evidence suggest that classic (5HT2A agonist) hallucinogens have clinically relevant effects in alcohol and drug addiction. Although recent studies have investigated the effects of psilocybin in various populations, there have been no studies on the efficacy of psilocybin for alcohol dependence. We conducted a single-group proof-of-concept study to quantify acute effects of psilocybin in alcohol-dependent participants and to provide preliminary outcome and safety data. Ten volunteers with DSM-IV alcohol dependence received orally administered psilocybin in one or two supervised sessions in addition to Motivational Enhancement Therapy and therapy sessions devoted to preparation for and debriefing from the psilocybin sessions. Participants' responses to psilocybin were qualitatively similar to those described in other populations. Abstinence did not increase significantly in the first 4 weeks of treatment (when participants had not yet received psilocybin), but increased significantly following psilocybin administration (p < 0.05). Gains were largely maintained at follow-up to 36 weeks. The intensity of effects in the first psilocybin session (at week 4) strongly predicted change in drinking during weeks 5-8 (r = 0.76 to r = 0.89) and also predicted decreases in craving and increases in abstinence self-efficacy during week 5. There were no significant treatment-related adverse events. These preliminary findings provide a strong rationale for controlled trials with larger samples to investigate efficacy and mechanisms. NCT02061293. © The Author(s) 2015.
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Despite suggestive early findings on the therapeutic use of hallucinogens in the treatment of substance use disorders, rigorous follow-up has not been conducted. To determine the safety and feasibility of psilocybin as an adjunct to tobacco smoking cessation treatment we conducted an open-label pilot study administering moderate (20 mg/70 kg) and high (30 mg/70 kg) doses of psilocybin within a structured 15-week smoking cessation treatment protocol. Participants were 15 psychiatrically healthy nicotine-dependent smokers (10 males; mean age of 51 years), with a mean of six previous lifetime quit attempts, and smoking a mean of 19 cigarettes per day for a mean of 31 years at intake. Biomarkers assessing smoking status, and self-report measures of smoking behavior demonstrated that 12 of 15 participants (80%) showed seven-day point prevalence abstinence at 6-month follow-up. The observed smoking cessation rate substantially exceeds rates commonly reported for other behavioral and/or pharmacological therapies (typically <35%). Although the open-label design does not allow for definitive conclusions regarding the efficacy of psilocybin, these findings suggest psilocybin may be a potentially efficacious adjunct to current smoking cessation treatment models. The present study illustrates a framework for future research on the efficacy and mechanisms of hallucinogen-facilitated treatment of addiction.
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Although psilocybin has been used for centuries for religious purposes, little is known scientifically about its acute and persisting effects. This double-blind study evaluated the acute and longer-term psychological effects of a high dose of psilocybin relative to a comparison compound administered under comfortable, supportive conditions. The participants were hallucinogen-naïve adults reporting regular participation in religious or spiritual activities. Two or three sessions were conducted at 2-month intervals. Thirty volunteers received orally administered psilocybin (30 mg/70 kg) and methylphenidate hydrochloride (40 mg/70 kg) in counterbalanced order. To obscure the study design, six additional volunteers received methylphenidate in the first two sessions and unblinded psilocybin in a third session. The 8-h sessions were conducted individually. Volunteers were encouraged to close their eyes and direct their attention inward. Study monitors rated volunteers' behavior during sessions. Volunteers completed questionnaires assessing drug effects and mystical experience immediately after and 2 months after sessions. Community observers rated changes in the volunteer's attitudes and behavior. Psilocybin produced a range of acute perceptual changes, subjective experiences, and labile moods including anxiety. Psilocybin also increased measures of mystical experience. At 2 months, the volunteers rated the psilocybin experience as having substantial personal meaning and spiritual significance and attributed to the experience sustained positive changes in attitudes and behavior consistent with changes rated by community observers. When administered under supportive conditions, psilocybin occasioned experiences similar to spontaneously occurring mystical experiences. The ability to occasion such experiences prospectively will allow rigorous scientific investigations of their causes and consequences.